Potentially active aspirin derivative to release nitric oxide: In-vitro, in-vivo and in-silico approaches.

The series of newer salicylate derivatives incorporating nitroxy functionality were synthesized and evaluated for their potential effect in gastrointestinal (GI) related toxicity produced by aspirin. The synthesized compounds (5a-j) were subjected to %NO (nitric oxide) release study, in-vitro anti-inflammatory potential, % inhibition of carrageenan-induced paw edema and the obtained results were validated by in-silico studies including molecular docking, MD simulations and in-silico ADME (absorption, distribution, metabolism, and elimination) calculations. Compounds 5a (20.86 %) and 5g (18.20 %) displayed the highest percentage of NO release in all the tested compounds. Similarly, 5a and 5h were found to have (77.11 % and 79.53 %) &(78.56 % and 66.10 %) inhibition in carrageenan induced paw edema in animal mode which were relatively higher than ibuprofen (standard used). The obtained results were validated by molecular docking and MD simulations studies. The molecular docking study of 5a and 5h revealed that docking scores were also obtained in very close proximity of -8.35, -9.67 and -8.48 for ibuprofen, 5g and 5h respectively. In MD simulations studies, the calculated lower RMSD (root mean square deviation) values 2.8 Å and 5.6 Å for 5g and 5h, respectively indicated the stability of ligand-protein complexes. Similarly lower RSMF (root mean square fluctuation) values indicated the molecules remained in the active pocket throughout the entire MD simulations run. Further, in-silico ADME calculations were determined and all compounds obey the Lipinski's rule of five and it was predicted that these molecules would be orally active without any serious toxic effect.

HSPiP, Computational Modeling, and QbD-Assisted Optimized Method Validation of 5-Fluorouracil for Transdermal Products.

This study addressed the simplest and most efficient HPLC (high-performance liquid chromatography) method for the estimation of 5-fluorouracil (5-FU) from rat blood plasma by implementing the Hansen solubility parameters (HSP), computation prediction program, and QbD (quality by design) tool. The mobile phase selection was based on the HSP predictions and experimental data. The Taguchi model identified seven variables (preoptimization) to screen two factors (mobile phase ratio as A and column temperature as B) at three levels as input parameters in "CCD (central composite design)" optimization (retention time as Y1 and peak area as Y2). The stability study (freeze-thaw cycle and short- and long-term stability) was conducted in the rat plasma. Results showed that HSPiP-based HSP values and computational model-based predictions were well simulated with the experimental solubility data. Acetonitrile (ACN) was relatively suitable over methanol as evidenced by the experimental solubility value, HSP predicted parameters (δh of 5-FU - δh of ACN = 8.3-8.3 = 0 as high interactive solvent whereas δh of 5-FU - δh of methanol = 8.3-21.7 = -13.4), and instrumental conditions. CCD-based dependent variables (Y1 and Y2) exhibited the best fit of the model as evidenced by a high value of combined desirability (0.978). The most robust method was adopted at A = 96:4 and B = 40 °C to get earlier Y1 and high Y2 as evidenced by high desirability (D) = 0.978 (quadratic model with p < 0.0023). The estimated values of LLOD and LLOQ were found to be 0.11 and 0.36 µg/mL, respectively with an accuracy range of 94.4-98.7%. Thus, the adopted method was the most robust, reliable, and reproducible methodology for pharmacokinetic parameters after the transdermal application of formulations in the rat.

Synthesis biological evaluation and molecular docking of isatin hybrids as anti-cancer and anti-microbial agents.

Isatin, known as 1H-indole-2,3-dione, was originally recognised as a synthetic molecule until its discovery in the fruits of the cannonball tree, Couroupita guianensis. It is naturally occurring in plants of the genus Isatis and serves as a metabolic derivative of adrenaline in humans. Isatin possesses significant pharmacological importance, and its synthetic versatility has prompted extensive interest in its derivative compounds due to their diverse biological and pharmacological properties. These derivatives represent a valuable class of heterocyclic compounds with potential applications as precursors for synthesizing numerous valuable drugs. In the pursuit of advancing our research on isatin hybrids, we investigate the utilisation of readily available hydrazonoindolin-2-one and isatin as starting materials for the synthesis of a wide range of analogues. Characterisation of the synthesized compounds was carried out through various analytical techniques. Furthermore, the obtained compounds were subjected to extensive testing to evaluate their anticancer and antimicrobial activities. Specifically, their efficacy against key proteins, namely Staphylococcus aureus protein (PDB ID: 1JIJ), Escherichia coli protein (PDB ID: 1T9U), Pseudomonas aeruginosa protein (PDB ID: 2UV0), and Acinetobacter baumannii protein (PDB ID: 4HKG), was examined through molecular docking calculations. Several molecules, such as 3, 4, 6, 16, and 19, displayed remarkable activity against the renal cancer cell line UO-31. Additionally, the results of antimicrobial activity testing revealed that compound 16 exhibited significant cytotoxicity against Candida albicans and Cryptococcus neoformans. Subsequently, ADME/T calculations were performed to gain insights into the potential effects and reactions of these molecules within human metabolism. This comprehensive study provides valuable insights into the potential pharmacological applications of isatin derivatives and underscores their significance in drug development.

HSPiP and QbD Program-Based Analytical Method Development and Validation to Quantify Ketoconazole in Dermatokinetic Study.

Ketoconazole (KTZ) is the most potential azole anti-mycotic drug. The quantification of KTZ from various layers of the skin after topical application of lipidic nanocarriers is critical. We addressed a sensitive, specific, simple, rapid, reproducible, and economic analytical method to quantify KTZ from the treated skin homogenate using the Hansen solubility parameter (HSP, HSPiP software)-based modeling and experimental design. The software provided various HSP values for KTZ and solvents to compose the mobile phase. The Taguchi model identified the significant sets of factors to develop a robust bioanalytical method with reduced variability. In the optimization, acetonitrile (ACN) concentration (X1 as A) and the pH of mobile phase (X2 as B) were two factors against two responses (Y1: peak area and Y2: retention time). The HPLC (high-performance liquid chromatography) method validation was carried out based on US-FDA guidelines for the developed KTZ formulations (suspension, solid nanoparticles, and commercial product) extracted from the treated rat skin. The experimental solubility of KTZ was found to be maximum in the two solvents (ACN and ethyl acetate), based on HSP values. Surface response methodology (SRM) identified remarkable impact of ACN concentration and the mobile phase pH on the peak area and retention time. Analytical limits (0.17 and 0.50 µg/mL) were established for KTZ-SLNs (extracted from the skin). The method was implemented with high reproducibility, accuracy, and selectivity to quantify KTZ from the treated rat skin.

Formulation of Silymarin-ß Cyclodextrin-TPGS Inclusion Complex: Physicochemical Characterization, Molecular Docking, and Cell Viability Assessment against Breast Cancer Cell Lines.

Silymarin (SIL) is a poorly water-soluble flavonoid reported for different pharmacological properties. Its therapeutic applications are limited due to poor water solubility. In this study, the solubility of silymarin has been enhanced by preparing freeze-dried binary and ternary complexes using beta cyclodextrin (ßCD) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). The stoichiometry of the drug and the carrier was selected from the phase solubility study. The dissolution study was performed to assess the effect of complexation on the release pattern of SIL. The formation of inclusion complexes was confirmed by different physicochemical studies. Finally, a cell viability assay (MCF 7; breast cancer cell line) was performed to compare the activity with free SIL. The phase solubilization results revealed the formation of a stable complex (binary) with a stability constant and complexation efficiency (CE) value of 288 mol L-1 and 0.045%. The ternary sample depicted a significantly enhanced stability constant and CE value (890 mol L-1 and 0.14%). The release study results showed a marked increase in the release pattern after addition of ßCD (alone) in the binary mixture (49.4 ± 3.1%) as well as inclusion complex (66.2 ± 3.2%) compared to free SIL (32.7 ± 1.85%). Furthermore, with the addition of TPGS in SIL-ßCD (ternary), the SIL release was found to be significantly enhanced from the SIL ternary mixture (79.2 ± 2.13%) in 120 min. However, fast SIL release was achieved with 99.2 ± 1.7% in 45 min for the SIL ternary complex. IR and NMR spectral analysis results revealed the formation of a stable complex with no drug-polymer interaction. The formation of complexes was also confirmed by the molecular docking study (docking scores of 4.1 and -6.4 kcal/mol). The in vitro cell viability result showed a concentration-dependent activity. The IC50 value of the SIL ternary complex was found to be significantly lower than that of free SIL. The findings of the study concluded that the prepared SIL inclusion complex can be used as an alternative oral delivery system to enhance solubility, dissolution, and biological activity against the tested cancer cell line.

Hansen Solubility Parameters and QbD-Oriented HPLC Method Development and Validation for Dermatokinetic Study of a Miconazole-Loaded Cationic Nanoemulsion in Rat Model.

Miconazole (MCZ) is a potential antifungal drug to treat skin infections caused by Candida, Tinea pedis (athlete's foot fungal infection), Tinea cruris (jock itching in the groin and buttocks), and Tinea corporis (red scaly rash on the skin). The current study focused on Hansen parameter-based solvent selection (HSPiP software) and method development optimization using an experimental design tool for sensitive, accurate, reproducible, economic, rapid, robust, and precise methodology to quantify MCZ in rat plasma. Moreover, a Taguchi design was used for screening two independent factors (flow rate and ACN content). Quality by design (QbD) was employed to optimize and identify the right ratio of mobile phase composition and its impact on the peak and retention time. The elution of MCZ was achieved using methanol and acetonitrile (15:85 v/v ratio) at a retention time of 6 min and optimal flow rate (1 mL/min). Finally, the method was validated based on accuracy, precision, linearity, selectiveness, and high recovery at varied concentrations as per the International Council for Harmonization (ICH) guidelines. The method was linear (r2 = 0.999) over the explored concentration range (250-2000 ng/mL) at 270 nm detection wavelength. The optimized method was used to quantify in vivo pharmacokinetic (PK) study after transdermal application of MCZ-loaded formulations (MCNE11, MNE11, MCZ-Sol, and MCZ-MKT). HSP-oriented solvent selection and quality by design-based optimized process variables and composition in the optimized analytical methodology were quite convincing and have been a cutting-edge MCZ analysis method so far. The validated method was robust, economic, and rapid with high specificity and selectivity.

Formulation of multicomponent inclusion complex of cyclodextrin-amino acid with Chrysin: Physicochemical characterization, cell viability and apoptosis assessment in human primary glioblastoma cell line.

Chrysin (CR) is a water-insoluble drug reported for different therapeutic effects. The microwave irradiation method was used in this study to create a multicomponent inclusion complex (CR-MC) containing CR (drug) and carrier hydroxyl propyl beta cyclodextrin (HP ß CD) and L-arginine (LA). The prepared inclusion complex (CR-MC) was evaluated for dissolution study and results were compared with chrysin physical mixture (CR-PM). Further, the samples were assessed for infra-red (IR), nuclear magnetic resonance (NMR), differential scanning calorimeter (DSC), scanning electron microscope (SEM) and molecular docking. Finally, the cell viability, reactive oxygen species and flow cytometer studies were also assessed to check the potential of the prepared inclusion complex on the human primary glioblastoma cell line (U87-MG cell). The phase solubility findings revealed a stability constant (773 mol L-1) as well as a complexation efficiency of 0.027. The dissolution study displayed a significant increase in CR release from CR-MC (99.03 ± 0.39%) > CR-PM (70.58 ± 1.16%) > pure CR (35.29 ± 1.55%). NMR and IR spectral data revealed no interaction between CR and carriers. SEM and DSC study results revealed the conversion into amorphous form. The molecular docking results illustrated a high docking score, which supports the findings of complex formation. The cell viability, reactive oxygen species, and flow cytometry studies results showed enhanced activity from CR-MC against the tested human primary glioblastoma cell line. From the results it has been observed that chrysin solubility significantly increased after complexation and there in vitro activity also enhanced against cancer cell line.

A correlation between oxidative stress and diabetic retinopathy: An updated review.

Oxidative stress (OS) is a cytopathic outcome of excessively generated reactive oxygen species (ROS), down regulated antioxidant defense signaling pathways, and the imbalance between the produced radicals and their clearance. It plays a role in the genesis of several illnesses, especially hyperglycemia and its effects. Diabetic retinal illness, a micro vascular side effect of the condition, is the prime reason of diabetic related blindness. The OS (directly or indirectly) is associated with diabetic retinopathy (DR) and related consequences. The OS is responsible to induce and interfere the metabolic signaling pathways to enhance influx of the polyol cascades and hexosamine pathways, stimulate Protein Kinase-C (PKC) variants, and accumulate advanced glycation end products (AGEs). Additionally, the inequity between the scavenging and generation of ROS is caused by the epigenetic alteration caused by hyperglycemia that suppresses the antioxidant defense system. Induced by an excessive buildup of ROS, retinal changes in structure and function include mitochondrial damage, cellular death, inflammation, and lipid peroxidation. Therefore, it is crucial to comprehend and clarify the mechanisms connected to oxidative stress that underlie the development of DR.

Mechanistic of Vesicular Ethosomes and Elastic Liposomes on Permeation Profiles of Acyclovir across Artificial Membrane, Human Cultured EpiDerm, and Rat Skin: In Vitro-Ex Vivo Study.

Acyclovir (ACV) controls cutaneous herpes, genital herpes, herpes keratitis, varicella zoster, and chickenpox. From previously reported ACV formulations, we continued to explore the permeation behavior of the optimized ACV loaded optimized ethosome (ETHO2R) and elastic liposome (ELP3R) and their respective carbopol gels across artificial membrane, cultured human EpiDerm, and rat skin. Transepidermal water loss (TEWL), scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and atomic force microscopy (AFM) were used to investigate the mechanistic perspective of permeation behavior. The size values of reformulated ELP3-R and ETHO2-R were observed as 217 and 128 nm, respectively (close to previous report), whereas their respective gels showed as 231 and 252 nm, respectively. ETHO2R showed high elasticity, %EE, and low vesicle size. These were investigated for the diffusion rate of the drug permeation (3 h) across the artificial membrane, cultured human EpiDerm, and rat skin. ETHO2GR showed the highest permeation flux (78.42 µg/cm2/h), diffusion coefficient (8.24 × 10-5 cm2/h), and permeation coefficient (0.67 × 10-3 cm/h) of ACV across synthetic membrane, whereas diffusion coefficient (2.4 × 10-4 cm2/h) and permeation coefficient (0.8 × 10-3 cm/h) were maximum across EpiDerm for ETHO2GR. ETHO2R suspension showed maximized permeation flux (169.58 µg/cm2/h) and diffusion rate (0.293 mg/cm2/h1/2), suggesting the rapid internalization of vesicles with cultured skin cells at low viscosity. A similar observation was revealed using rat skin, wherein the permeation flux (182.42 µg/cm2/h), permeation coefficient (0.3 × 10-2 cm/h), and diffusion rate (0.315 mg/cm2/h1/2) of ETHO2R were relatively higher than ELP3R and ELP3GR. Relative small size (128 nm), low viscosity, ethanol-mediated ultra-deformability, high drug entrapment (98%), and elasticity (63.2) are associated with ETHO2R to provide remarkable permeation behavior across the three barriers. The value of TEWL for ETHO2R (21.9 g/m2h) was 3.71 times higher than untreated control (5.9 g/m2h), indicating ethanol-mediated maximized surficial skin lipid perturbation at 3 h of application, whereas the respective ETHO2GR-treated rat skin had TEWL value (18.6 g/m2h) slightly lower than ETHO2R due to gel-based hydration into the skin. SEL, CLSM, and AFM provided a mechanistic perspective of ETHO2R and ELP3R-mediated permeation across rat skin and carrier-mediated visualization (skin-vesicle interaction). AFM provided detailed nanoscale surface roughness topographical parameters of treated and untreated rat skin as supportive data to SEM and CLSM. Thus, ethosomes ETHO2R and respective gel assisted maximum permeation of ACV across rat skin and cultured human EpiDerm to control cutaneous herpes infection and herpes keratitis.

GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans.

Oral and parenteral delivery routes of valproic acid (VA) are associated with serious adverse effects, high hepatic metabolism, high clearance, and low bioavailability in the brain. A GastroPlus program was used to predict in vivo performance of immediate (IR) and sustained release (SR) products in humans. HSPiP software 5.4.08 predicted excipients with maximum possible miscibility of the drug. Based on the GastroPlus and HSPiP program, various excipients were screened for experimental solubility, nanoemulsions, and respective gel studies intended for nasal-to-brain delivery. These were characterized by size, size distribution, polydispersity index, zeta potential, morphology, pH, % transmittance, drug content, and viscosity. In vitro drug release, ex vivo permeation profile (goat nasal mucosa), and penetration studies were conducted. Results showed that in vivo oral drug dissolution and absorption were predicted as 98.6 mg and 18.8 mg, respectively, from both tablets (IR and SR) at 8 h using GastroPlus. The predicted drug access to the portal vein was substantially higher in IR (115 mg) compared to SR (82.6 mg). The plasma drug concentration-time profile predicted was in good agreement with published reports. The program predicted duodenum and jejunum as the prime sites of the drug absorption and no effect of nanonization on Tmax for sustained release formulation. Hansen parameters suggested a suitable selection of excipients. The program recommended nasal-to-brain delivery of the drug using a cationic mucoadhesive nanoemulsion. The optimized CVE6 was associated with the optimal size (113 nm), low PDI (polydispersity index) (0.26), high zeta potential (+34.7 mV), high transmittance (97.8%), and high strength (0.7% w/w). In vitro release and ex vivo permeation of CVE6 were found to be substantially high as compared to anionic AVE6 and respective gels. A penetration study using confocal laser scanning microscopy (CLSM) executed high fluorescence intensity with CVE6 and CVE6-gel as compared to suspension and ANE6. This might be attributed to the electrostatic interaction existing between the mucosal membrane and nanoglobules. Thus, cationic nanoemulsions and respective mucoadhesive gels are promising strategies for the delivery of VA to the brain through intransal administration for the treatment of seizures and convulsions.

Formulation of Piperine-Loaded Nanoemulsion: In Vitro Characterization, Ex Vivo Evaluation, and Cell Viability Assessment.

Piperine is an alkaloid, but its therapeutic efficacy is limited due to poor aqueous solubility. In this study, piperine nanoemulsions were prepared using oleic acid (oil), Cremophore EL (surfactant), and Tween 80 (co-surfactant) using the high-energy ultrasonication approach. The optimal nanoemulsion (N2) was further evaluated using transmission electron microscopy, release, permeation, antibacterial, and cell viability studies based on minimal droplet size and maximum encapsulation efficiency. The prepared nanoemulsions (N1-N6) showed a transmittance of more than 95%, a mean droplet size between 105 ± 4.11 and 250 ± 7.4 nm, a polydispersity index of 0.19 to 0.36, and a ζ potential of -19 to -39 mV. The optimized nanoemulsion (N2) showed significantly improved drug release and permeation compared with pure piperine dispersion. The nanoemulsions were stable in the tested media. The transmission electron microscopy image showed a spherical and dispersed nanoemulsion droplet. The antibacterial and cell line results of piperine nanoemulsions were significantly better than the pure piperine dispersion. The findings suggested that piperine nanoemulsions may be a more advanced nanodrug delivery system than conventional ones.

Biogenic nanoparticles from waste fruit peels: Synthesis, applications, challenges and future perspectives.

Nanotechnology is a continually growing field with a wide range of applications from food science to biotechnology and nanobiotechnology. As the current world is grappling with non-biodegradable waste, considered more challenging and expensive to dispose of than biodegradable waste, new technologies are needed today more than ever. Modern technologies, especially nanotechnology, can transform biodegradable waste into products for human use. Researchers are exploring sustainable pathways for nanotechnology by utilizing biodegradable waste as a source for preparing nanomaterials. Over the past ten years, the biogenic production of metallic nanoparticles (NPs) has become a promising alternative technique to traditional NPs synthesis due to its simplicity, eco-friendliness, and biocompatibility in nature. Fruit and vegetable waste (after industrial processing) contain various bioactives (such as flavonoids, phenols, tannins, steroids, triterpenoids, glycosides, anthocyanins, carotenoids, ellagitannins, vitamin C, and essential oils) serving as reducing and capping agents for NP synthesis and they possess antibacterial, antioxidant, and anti-inflammatory properties. This review addresses various sources of biogenic NPs including their synthesis using fruit/vegetable waste, types of biogenic NPs, extraction processes and extracted biomaterials, the pharmacological functionality of NPs, industrial aspects, and future perspectives. In this manner, this review will cover the most recent research on the biogenic synthesis of NPs from fruit/vegetable peels to transform them into therapeutic nanomedicines.

HPV pathogenesis, various types of vaccines, safety concern, prophylactic and therapeutic applications to control cervical cancer, and future perspective.

Over 98% of cervical cancers (CC) are caused by regular infections with "high risk" genotype of the human papilloma virus (HPV). However, this is not always the causative factor. Therefore, production of HPV vaccinations represents a significant chance to minimize the risk of CC. Phase III studies for a number of preventative HPV vaccines based on L1-virus-like particle (VLPs) have just been completed and the preliminary results are very convincing. However, there are a lot of practical concerns that need to be resolved before the use of these vaccinations. These vaccines were challenged with obvious queries such as protection time, subject receiving vaccines, time of vaccination, and how to include them into ongoing screening programs. Although these vaccines were 90% effective at preventing HPV infection as these offered only modest advantages for the removal of pre-existing infections. New advancements in the creation of therapeutic vaccinations have been explored for further improvement and post-vaccination surveillance. Therapeutic vaccines attempted to boost cell-mediated immunities and these are detrimental to the infected cell as opposed to neutralizing antibodies (different from prophylactic vaccines).

Optimized Green Nanoemulsions to Remove Pharmaceutical Enoxacin from Contaminated Bulk Aqueous Solution.

We attempted to develop green nanoemulsions (ENE1-ENE5) using capryol-C90 (C90), lecithin, Tween 80, and N-methyl-2-pyrrolidone (NMP). HSPiP software and experimentally obtained data were used to explore excipients. ENE1-ENE5 nanoemulsions were prepared and evaluated for in vitro characterization parameters. An HSPiP based QSAR (quantitative structure-activity relationship) module established a predictive correlation between the Hansen solubility parameter (HSP) and thermodynamic parameters. A thermodynamic stability study was conducted under stress conditions of temperature (from -21 to 45 °C) and centrifugation. ENE1-ENE5 were investigated for the influence of size, viscosity, composition, and exposure time on emulsification (5-15 min) on %RE (percent removal efficiency). Eventually, the treated water was evaluated for the absence of the drug using electron microscopy and optical emission spectroscopy. HSPiP program predicted excipients and established the relationship between enoxacin (ENO) and excipients in the QSAR module. The stable green nanoemulsions ENE-ENE5 possessed the globular size range of 61-189 nm, polydispersity index (PDI) of 0.1-0.53, viscosity of 87-237 cP, and ζ potential from -22.1 to -30.8 mV. The values of %RE depended upon the composition, globular size, viscosity, and exposure time. ENE5 showed %RE value as 99.5 ± 9.2% at 15 min of exposure time, which may be due to the available maximized adsorption surface. SEM-EDX (scanning electron microscopy-X-ray dispersive energy mode) and inductively coupled plasma-optical emission spectroscopy (ICP-OES) negated the presence of ENO in the treated water. These variables were critical factors for efficient removal of ENO during water treatment process design. Thus, the optimized nanoemulsion can be a promising approach to treat water contaminated with ENO (a potential pharmaceutical antibiotics).

Effects of Black Cumin Seed (Nigella sativa) and Coconut Meals (Cocos nucifera) on Broiler Performance and Cecal Microbiota.

The objective of this study was to investigate the effect of dietary supplementation with black cumin seed meal (BCSM) and coconut meal (CM) on the performance and cecal microbiota of Cobb 500 hybrid broilers. The study was conducted on 600 chicks on the first day of hatching; the chicks were randomly distributed equally into 12 equal-sized floor pens. Four dietary treatments (C, T1, T2 and T3) were replicated three times (50 chicks/replicate): C was the control group; T1 was supplemented with 10% BCSM; T2 was supplemented with 10% CM; T3 was supplemented with 5% BCSM and 5% CM. At slaughter age on day 35, our findings showed that treatment T2 increased significantly body weight and feed conversion ratio (FCR) compared to C, T1 and T3. In addition, the hot carcass dressing percentages in treatments T1, T2, and T3 were significantly higher than that of the C group. The results of relative normalized comparative gene expression of Clostridioides difficile, Roseburia and Streptococcus were not significantly changed in all treatments (p > 0.05). Treatment T1 resulted in a significant decrease in gene expression of the entire microbiota, while treatment T2 resulted in a significant increase in gene expression of all microbes, leading to an enriched and diverse microbial community. It can be concluded that supplementation with 10% BCSM is beneficial in inhibiting pathogenic microbes during early post-hatch days. In contrast, CM may promote and enhance the diversity of microbial communities during broiler growth. The inclusion of non-conventional feed ingredients in poultry diets may improve growth performance and may reduce the cost of broiler feed.

Identification of Potential Antitubulin Agents with Anticancer Assets from a Series of Imidazo[1,2-a]quinoxaline Derivatives: In Silico and In Vitro Approaches.

Computer-aided drug design is a powerful and promising tool for drug design and development, with a reduced cost and time. In the current study, we rationally selected a library of 34 fused imidazo[1,2-a]quinoxaline derivatives and performed virtual screening, molecular docking, and molecular mechanics for a lead identification against tubulin as an anticancer molecule. The computational analysis and pharmacophoric features were represented as 1A2; this was a potential lead against tubulin, with a maximized affinity and binding score at the colchicine-binding site of tubulin. The efficiency of this lead molecule was further identified using an in vitro assay on a tubulin enzyme and the anticancer potential was established using an MTT assay. Compound 1A2 (IC50 = 4.33-6.11 µM against MCF-7, MDA-MB-231, HCT-116, and A549 cell lines) displayed encouraging results similar to the standard drug colchicine in these in vitro studies, which further confirmed the effectiveness of CADD in new drug developments. Thus, we successfully applied the utility of in silico techniques to identify the best plausible leads from the fused azaheterocycles.

Strategic nanocarriers to control neurodegenerative disorders: Concept, challenges, and future perspective.

Various neurodegenerative diseases (parkinson, huntington, alzheimer, and amyotrophic lateral sclerosis) are becoming serious global health challenges. Despite various treatment options, successful delivery and effective outcomes have been challenged with several physiological-anatomical barriers, formulation related issues, post-administration hurdles, regulatory constraints, physical hurdles, environmental issues, and safety concern. In the present review, we addressed a brief understanding of pathological and normal condition of blood brain barrier (BBB), rational for brain delivery using nanocarriers, major challenges, advantages of nanomedicine, critical aspects of nanomedicine to translate from bed to clinics, and strategic approaches for improved delivery across BBB. The review addressed various mechanistic perspective for delivery of drug loaded nanocarriers across BBB. Moreover, several reports have been published wherein phytomedicine, exosomes, magnetic nanopartilces, functionalized nanocarriers, cationic nanopartilces, and nano-phytomedicine were investigated for remarkable improvement in neurological disorders. These findings are informative for healthcare professionals, researchers, and scientists working in the domains. The successful application and convincing outcomes of nanomedicines were envisaged with clinical trials conducted on various drugs intended to control neurological disorders (NDs). Conclusively, the review addressed comprehensive findings on various aspects of drug loaded nanocarrier delivery across BBB, considerable risks, potential therapeutic benefits, clinical trial based outcomes, and recent advances followed by future perspectives.

Hydroethanolic Extract of Urtica dioica L. (Stinging Nettle) Leaves as Disaccharidase Inhibitor and Glucose Transport in Caco-2 Hinderer.

Herbal treatment for diabetes mellitus is widely used. The pharmacological activity is thought to be due to the phenolic compounds found in the plant leaves. The present study aims to investigate the phytochemical composition of Urtica dioica (UD) hydroethanolic extract and to screen its antidiabetic activity by disaccharidase hindering and glucose transport in Caco-2 cells. The results have shown that a total of 13 phenolic compounds in this work, viz. caffeic and coumaric acid esters (1, 2, 4-7, 10), ferulic derivative (3), and flavonoid glycosides (8, 9, 11-13), were identified using HPLC-DAD-ESI/MS2. The most abundant phenolic compounds were 8 (rutin) followed by 6 (caffeoylquinic acid III). Less predominant compounds were 4 (caffeoylquinic acid II) and 11 (kaempferol-O-rutinoside). The UD hydroethanolic extract showed 56%, 45%, and 28% (1.0 mg/mL) inhibition level for maltase, sucrase, and lactase, respectively. On the other hand, glucose transport was 1.48 times less at 1.0 mg/mL UD extract compared with the control containing no UD extract. The results confirmed that U. dioica is a potential antidiabetic herb having both anti-disaccharidase and glucose transport inhibitory properties, which explained the use of UD in traditional medicine.

Formulation of Multicomponent Chrysin-Hydroxy Propyl ß Cyclodextrin-Poloxamer Inclusion Complex Using Spray Dry Method: Physicochemical Characterization to Cell Viability Assessment.

The work aimed to enhance chrysin (CHR) water solubility, dissolution, and in vitro antibacterial as well as cell viability. Chrysin binary, as well as ternary inclusion complex, were prepared using the spray drying method. The influence of an auxiliary component (poloxamer; PLX) was also assessed after being incorporated into the chrysin HP ßCD complex (CHR-BC) and formed as a chrysin ternary complex (CHR-TC). The phase solubility investigation was carried out in order to assess the complexation efficiency and stability constant. The samples were assessed for the dissolution test, physicochemical evaluation, antibacterial activity, and cell viability tests were also assessed. The results of the phase solubility investigation showed that the stability constant for the binary system (268 M-1) was lower than the ternary system (720 M-1). The complex stability was validated by the greater stability constant value. The dissolution results showed that pure CHR had a limited release of 32.55 ± 1.7% in 60 min, while prepared CHR-TC and CHR-BC both demonstrated maximum CHR releases of 99.03 ± 2.34% and 71.95 ±2.1%, respectively. The dissolution study's findings revealed that the release of CHR was much improved over that of pure CHR. A study using a scanning electron microscope showed that CHR-TC contains more agglomerated and amorphous components. The higher conversion of crystalline CHR into an amorphous form is responsible for the structural alterations that are observed. After complexation, the distinctive peaks of pure CHR changed due to the complexation with HP ßCD and PLX. The antimicrobial and cell viability results revealed improved antimicrobial activity as well as a lower IC50 value than pure CHR against the tested anticancer cell line (MCF7).

Improved Subcutaneous Delivery of Ketoconazole Using EpiDerm and HSPiP Software-Based Simulations as Assessed by Cell Viability, Cellular Uptake, Permeation, and Hemolysis In Vitro Studies.

Ketoconazole (KETO) is the drug of choice to control local, systemic, and resistant types of fungal infections. Subcutaneous (sub-Q) delivery offers several benefits. The present study investigated the sub-Q delivery of KETO using HSPiP software based on optimized concentrations of dimethylacetamide (DMA) in binary solvents (DMA + water), in vitro cellular uptake (J774A.1) assays, cellular toxicity (L929), and in vitro hemolysis studies. Results showed that the estimated permeation coefficient (9.6 × 10-3 cm/h) and diffusion coefficient (3.9 × 10-3 cm2/h) of KETO (22.3 mg) in KF3 (300 mg of DMA + water) across EpiDerm were relatively higher as compared to the other formulations [KF1 (11.2 and 150 mg as KETO and DMA, respectively) and KF2 [(22.3 and 300 mg as KETO and DMA, respectively)] due to the increased content of DMA and KETO. HSPiP simulated and predicted the impact of constant and variable diffusion coefficients on the percent drug absorption across EpiDerm and the time needed to achieve equilibrium. The concentration-dependent diffusion coefficient fed into HSPiP predicted that the drug absorption and permeation values were linearly dependent on the square root of time. The HSPiP predicted permeation flux values from KF3, KF2, and KF1 across the EpiDerm were 4.07 × 10-6, 4.01 × 10-6, and 1.1 × 10-6 g/cm2/s, respectively, at respective D range values. The selected K30G (324 mOsm/Kg) showed an optimal pH (6.9) and minimum drug loss (0.01%) over a period of 1 month at room temperature. KG30 was found to be less toxic to normal L292 cells and caused maximum cytotoxicity to candida cells residing within infected macrophage cells (J774A.1 incubated for 24 h), which was attributed to the slow diffusion of K30G compared to DS (the drug solution with an equivalent concentration). KG30 elicited substantial internalization with candida albicans (MTCC 4748) compared to the control group (24 h). Lastly, in vitro hemolysis studies (1 and 5 µg/mL) corroborated the safety of K30G for sub-Q delivery. Therefore, this new formulation and approach for delivering KETO is a promising alternative to conventional products to control fungal infections and, thus, should be further studied in vivo.